The inflammasome is a large, multimeric protein complex found primarily in innate immune cells, which are white blood cells that can attack a wide range of pathogenic threats. Three main elements make up the inflammasome: 1) the sensor – a cytosolic pattern recognition receptor that senses pathogen- or damage-associated molecular patterns (PAMPs and DAMPs), 2) an adaptor protein called ASC, and 3) a caspase effector that cleaves and activates pro-IL-1 beta and pro-IL-18.

Prior to inflammasome activation, a cell must first be "primed" with PAMP/DAMP signaling, which transcriptionally upregulates both IL-1 beta and the inflammasome sensor. When a primed cell receives an additional PAMP/DAMP stimulus, the inflammasome complex assembles and initiates a proteolytic cascade leading to cleavage and release of IL-1 beta and IL-18. Often a form of inflammatory programmed cell death called pyroptosis ensues.

Inflammasome signaling is a surefire way to initiate inflammation in response to tissue damage or infectious threats; however, uncontrolled inflammasome activation can wreak havoc in healthy tissues, including the central nervous system (CNS).

Inflammation in the central nervous system

Contrary to historical belief, the CNS is susceptible to inflammation. In fact, many, if not all, neurodegenerative diseases are characterized by major immune-mediated pathology.

Inflammasome activation in the CNS is primarily orchestrated by CNS-resident macrophages called microglia or infiltrating immune cells1. As the initial inflammatory stimulus is amplified by cell death and cytokine release, it leads to tissue damage, blood-brain barrier leakage, and enhanced immune cell trafficking.

Amyotrophic lateral sclerosis (ALS) is the disease behind the "ice-bucket challenge" that became an internet sensation a few years ago. NLRP3 (one of the most well-studied inflammasome sensors) and ASC have been detected in the spinal cords of ALS patients, suggesting an increase in inflammasome assembly and activity2. In mouse models of ALS, mice lacking IL-1beta or caspase-1 have slower onset of disease, suggesting that inflammasome activation is exacerbating pathology, but may not be driving it3.

Interestingly, inflammasome activation has been linked to epileptic seizures, as pharmacological blockade of IL-1 can prevent experimentally induced seizures in rodents, and blocking either NLRP1 or NLRP3 can attenuate symptoms4-6.

Aberrant inflammasome signaling has also been implicated in Alzheimer’s disease, strokes, multiple sclerosis, Parkinson’s disease, and acute brain trauma, among other neuroinflammatory disorders1.

Targeting the inflammasome to treat neuroinflammatory disorders

Pharmacological blockade of inflammasome activation seems like an obvious step forward to treat neuroinflammatory diseases, but presents some unique challenges. Because inflammasome activation drives multiple downstream signaling cascades, inhibiting it early enough to have an effect can be tricky. For example, blocking IL-1 signaling or caspase-1 activation in rodent stroke models is protective, but only if the treatment is administered within 3 hours post-stroke7-8.

There are already several FDA-approved, protein-based drugs that can block IL-1 signaling. Unfortunately, these drugs have difficulty crossing the blood-brain barrier and cannot inhibit the other consequences of inflammasome activation, like IL-18 release and pyroptosis, making them suboptimal for treating CNS-inflammasome conditions1.

A number of small-molecule inflammasome inhibitors have recently been shown to attenuate disease severity in animal models of neurodegenerative diseases, and may prove to be more promising options for treating human conditions in the future1.